Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis

Our plain-English summary of Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis, by Y. Wang, A.K. Rishi, W. Wu, et al (Molecular and Cellular Biochemistry, 2011).

The study

• Authors: Y. Wang, A.K. Rishi, W. Wu, L. Polin, S. Sharma, E. Levi, S. Albelda, H.I. Pass, A. Wali
• Journal: Molecular and Cellular Biochemistry
• Published: 2011;357(1-2):83-94
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related malignancy of the thoracic pleura. Although, platinum-based agents are the first line of therapy, there is an urgent need for second-line therapies to treat the drug-resistant MPM. Cell cycle as well as apoptosis pathways are frequently altered in MPM and thus remain attractive targets for intervention strategies. Curcumin, the major component in the spice turmeric, alone or in combination with other chemotherapeutics has been under investigation for a number of cancers. In this study, we investigated the biological and molecular responses of MPM cells to curcumin treatments and the mechanisms involved. Flow-cytometric analyses coupled with western immunoblotting and gene-array analyses were conducted to determine mechanisms of curcumin-dependent growth suppression of human (H2373, H2452, H2461, and H226) and murine (AB12) MPM cells. Curcumin inhibited MPM cell growth in a dose- and time-dependent manner while pretreatment of MPM cells with curcumin enhanced cisplatin efficacy. Curcumin activated the stress-activated p38 kinase, caspases 9 and 3, caused elevated levels of proapoptotic proteins Bax, stimulated PARP cleavage, and apoptosis. In addition, curcumin treatments stimulated expression of novel transducers of cell growth suppression such as CARP-1, XAF1, and SULF1 proteins. Oral administration of curcumin inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating apoptosis. Thus, curcumin targets cell cycle and promotes apoptosis to suppress MPM growth in vitro and in vivo. Our studies provide a proof-of-principle rationale for further in-depth analysis of MPM growth suppression mechanisms and their future exploitation in effective management of resistant MPM.

In plain English

This was a laboratory study of curcumin, the main component of the spice turmeric, on malignant pleural mesothelioma cells. It did not study people or asbestos exposure. The authors tested four human mesothelioma cell lines (H2373, H2452, H2461 and H226) and one mouse line (AB12). Curcumin reduced growth of all the cell lines more as the dose rose. The dose that halved growth was about 20 to 25 micromolar in the human cells and about 25 micromolar in the mouse cells. Curcumin given before the chemotherapy drug cisplatin increased cisplatin's growth-inhibiting effect in H2373 and H2452 cells, but gave only modest inhibition in H2461 cells. In H2373 cells, curcumin raised levels of Bax, CARP-1 and XAF1, proteins linked to programmed cell death (apoptosis). It also raised SULF1, which the authors called a putative tumor suppressor. In mice carrying tumors grown from AB12 cells, curcumin given daily by mouth suppressed tumor growth. No visible toxicity was seen. The authors concluded that curcumin suppressed mesothelioma growth in cells and in mice. They said several questions about how it works remained to be clarified.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: experiments on mesothelioma cell lines (in vitro) and a mouse tumor experiment (in vivo)
• Who was studied: Human malignant pleural mesothelioma cell lines H2373, H2452 and H2461 (patient-derived, established in the authors' laboratory) and H226 (from ATCC); the mouse mesothelioma cell line AB12; and female BALB/c mice aged 5 weeks injected under the skin with AB12 cells (methods state n = 5 per group)
• Exposure: Curcumin at various doses in cell culture, alone or before cisplatin. In mice, 500 mg/kg curcumin daily by oral gavage, compared with vehicle (DMSO). No asbestos exposure was studied.
• Main results:
  • The concentration of curcumin that halved growth (IC50) was about 20–25 micromolar in the human mesothelioma cell lines
  • In the mouse AB12 mesothelioma cells, the IC50 was about 25 micromolar
  • 20 micromolar curcumin for 48 hours caused about 60%, 60%, 50% and 30% growth inhibition of H2373, H2452, H2461 and H226 cells, respectively
  • Curcumin pretreatment enhanced cisplatin's growth inhibition in H2373 and H2452 cells
  • The combination of 10 micromolar doses of curcumin and cisplatin produced only modest growth inhibition of H2461 cells
  • In H2373 cells, curcumin alone did not change the cell cycle distribution
  • In H2373 cells, curcumin combined with cisplatin led to accumulation of cells in the apoptotic (sub G0) fraction
  • In H2373 cells, curcumin increased the pro-apoptotic protein Bax, along with cleaved caspase 3, caspase 9 and PARP
  • Mouse AB12 cells needed a higher curcumin dose (50 micromolar) to activate apoptosis signaling than H2373 cells (10 micromolar)
  • In gene-array analysis of H2373 and H2461 cells, curcumin lowered expression of several growth-promoting genes
  • In gene-array analysis, curcumin raised expression of growth-inhibitory genes, and western blots showed elevated XAF1 and SULF1 proteins
  • The authors described SULF1 as a putative tumor suppressor, separately from the apoptosis transducers XAF1 and CARP-1
  • Western blots showed curcumin increased CARP-1 protein in the MPM cells
  • In mice with AB12-derived tumors, oral curcumin suppressed tumor growth (tumor volume and weight data shown only in figures)
  • Treated mice showed no visible toxicity
  • Tumors from curcumin-treated mice had more apoptotic (TUNEL-positive) cells
• The authors' conclusion: The authors concluded that curcumin suppressed mesothelioma growth in cell culture and in mice, and enhanced the effect of cisplatin, in part by stimulating apoptosis; they described the work as proof-of-concept
• Limitations the authors state:
  • The authors stated that why mouse cells needed a higher curcumin dose than human cells remained to be clarified
  • The authors stated that whether, and how far, curcumin interferes with cell cycle progression by lowering ID proteins remained to be clarified

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Apoptosis, Pleural Mesothelioma, Pleura, Cisplatin.

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